In recent years, new types of neoplasia inhibitors have been emerging. Such compounds selectively induce apoptosis (a form of cell death) in neoplastic, but not in normal cells. Neoplasia—which includes both precancerous and cancerous conditions—was historically treated chemotherapeutically only at the cancerous stage. Treatment with chemotherapeutics induced cell death (whether by apoptosis or necrosis) in rapidly proliferating cells indiscriminately (i.e., whether those cells were neoplastic or normal). As a result, most conventional chemotherapeutics caused significant cell death in normal tissues such as hair follicles, intestinal lining, skin and the like, that regenerate rapidly in the body. The side effects (e.g., hair loss, and skin and digestive disorders) of such conventional chemotherapeutics reflect non-specific cell death. As a result, conventional chemotherapeutics are used only on an acute (i.e., short-term) basis.
Because conventional chemotherapeutics non-specifically induce cell death, in both neoplastic and normal cells, such compounds, are not recommended for use against precancerous conditions even in patients with the most severe forms of precancerous conditions. For example, in familial polyposis patients—who can each form thousands of colonic polyps—surgical removal of the colon is standard practice (because of the extremely high cancer risk) whereas conventional chemotherapy is virtually unheard of.
As reported in pending U.S. patent application Ser. No. 09/664,035 filed Sep. 18, 2000 (Method For Identifying Compounds For Inhibition Of Cancerous Lesions, Pamukcu, et al. (Case No. P-119 CIP-3)), which is incorporated herein by reference, the selective neoplasia inhibitors described therein induce apoptosis in neoplastic cells, but not in normal proliferating cells. Thus, as reported in Ser. No. 09/664,035 (Case No. P-119 CIP-3), even patients with precancerous lesions can take such inhibitors without the side effects of conventional chemotherapeutics. Given the other attributes of such compounds, they can be taken by patients even on a chronic (i.e., long-term) basis. As reported in that application, a common attribute of such selective neoplasia inhibitors is that they inhibit cyclic GMP (cGMP)-specific phosphodiesterases (PDEs). cGMP-specific PDEs include the GMP-binding, cyclic GMP-specific phosphodiesterase (designated cGB-PDE) which is a phosphodiesterase gene family 5 isoenzyme (hereinafter “PDE5”). PDE5 is described more fully, inter alia, by Beavo, et al., in U.S. Pat. Nos. 5,652,131 and 5,702,936, that are incorporated herein by reference. Phosphodiesterase gene families 6 and 9 are also cGMP-specific isoforms. Another cGMP-specific PDE is the novel PDE found in neoplastic cells described by Liu, et al., in issued U.S. Pat. No. 6,200,771, entitled A Novel Cyclic GMP-Specific Phosphodiesterase And Methods For Using Same In Pharmaceutical Screening For Identifying Compounds For Inhibition Of Neoplastic Lesions (Case No. P-143), which is incorporated herein by reference. The novel cGMP-specific PDE described in that application is distinct from PDE5 and is broadly characterized by:                (a) cGMP specificity over cAMP;        (b) positive cooperative kinetic behavior in the presence of cGMP substrate;        (c) submicromolar affinity for cGMP; and        (d) insensitivity to incubation with purified cGMP-dependent protein kinase.        
For general background on phosphodiesterases, see, Beavo, J. A. (1995) Cyclic Nucleotide Phosphodiesterases: Functional Implications of Multiple Isoforms, Physiological Reviews 75:725-747; and the web site <http://weber.u.washington.edu/˜pde/pde.html>(November 1998).